Intrauterine growth restriction (IUGR) is a major health problem in the United States and worldwide. However, currently there are no effective treatments to prevent or reverse IUGR. Our long-range goal is to optimize fetal growth and development. The objective of this exploratory R21 application is to narrow the focus of our new research direction and guide the design of future mechanistic studies of IUGR in response to undernutrition. The hypothesis of this application is that reduced placental growth (including vascular growth), which results in reduced utero-placental blood flows and placental transfer of nutrients to the fetus, is the likely cause of IUGR in underfed dams. This hypothesis has been formulated on the basis of our current knowledge that 1) nitric oxide (NO, a major angiogenic factor) and polyamines (key regulators of cell proliferation), which are produced from arginine, play critical roles in placental growth (including vascular growth); 2) tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis; and 3) concentrations of both arginine and BH4 are reduced in the placenta and fetal plasma of underfed ewes. We will use an established ovine model of IUGR to pursue the specific aims of increasing fetal growth in underfed ewes through infusion of arginine or BH4 into the uterine artery. The proposed research is innovative, because 1) we put forward a new hypothesis that impaired placental synthesis of NO and polyamines may provide a biochemical basis for IUGR in response to maternal undernutrition; 2) we propose to test this hypothesis and solve a complex nutritional, reproductive, and vascular problem using a unique multidisciplinary approach; and 3) the proposed research is the first venture to determine if increasing arginine or BH4 provision will increase placental transfer of nutrients to the fetus, thereby preventing IUGR in underfed dams. Increasing placental NO and polyamine synthesis through arginine or BH4 administration may provide a novel, useful tool to reverse or ameliorate IUGR in both human medicine and animal agriculture. Thus, findings from this R21 project will greatly advance the understanding of mechanisms for fetal growth, and will also have broad impact on reproductive health. Providing an optimal intrauterine environment will not only ensure optimal fetal growth and development, but will also reduce the risk of chronic diseases in adults. This will ultimately promote favorable pregnancy outcomes while saving billions of healthcare dollars in the U.S. and worldwide. [unreadable] [unreadable] [unreadable]